Phenotypic diversity of its constituent cells is a hallmark of the nervous system. This characteristic is the fabric underlying the complexities of normal nervous system function as well as a variety of neurological disorders. The three projects comprising our proposed program share the goal of understanding how this remarkable degree of diversity is generated during neurodevelopment. The main thrust of this revised renewal program project grant application is an integrated, multidisciplinary assault on developmental gene neurobiological problems. We will conduct studies of neuronal determination, regulation of developmental gene expression, and epigenetic influences on neuronal differentiation. Dr. Paul Salvaterra is interested in the molecular logic that regulates neuronal determination. He will study the regulation of a neuron specific gene in the developing nervous system of Drosophila. Dr. Linda Iverson is interested in the regulation of gene expression during the differentiation of voltage-gated ion channels. She will examine the expression of the Drosophila gene Shaker that encodes functionally distinct potassium channels. Dr. James Vaughn is interested in the role of cellular interactions in the differentiation of neuronal phenotypes. He will study the migration of four subsets of cholinergic neurons in rat spinal cord to see whether these neurons develop their diverse characteristics in response to epigenetic cues encountered on different migration pathways. While the main focus of this program- project is on normal development, we anticipate that it will contribute information that is fundamental to understanding neurological and neuromuscular disorders.